Coating for a stent and a method of forming the same

ABSTRACT

A coating for a stent and methods for coating a stent are provided. The coating may be used for the sustained delivery of an active ingredient or a combination of active ingredients.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The invention relates to implantable devices or endoluminalprostheses, such as stents. More particularly, this invention relates toa coating for a stent and methods for making the same.

[0003] 2. Description of the Background

[0004] Percutaneous transluminal coronary angioplasty (PTCA) is aprocedure for treating heart disease. A catheter assembly having aballoon portion is introduced percutaneously into the cardiovascularsystem of a patient via the brachial or femoral artery. The catheterassembly is advanced through the coronary vasculature until the balloonportion is positioned across the occlusive lesion. Once in positionacross the lesion, the balloon is inflated to a predetermined size toradially press against the atherosclerotic plaque of the lesion forremodeling of the vessel wall. The balloon is then deflated to a smallerprofile to allow the catheter to be withdrawn from the patient'svasculature.

[0005] A problem associated with the above procedure includes formationof intimal flaps or torn arterial linings, which can collapse andocclude the conduit after the balloon is deflated. Vasospasms and recoilof the vessel wall also threaten vessel closure. Moreover, thrombosisand restenosis of the artery may develop over several months after theprocedure, which may necessitate another angioplasty procedure or asurgical by-pass operation. To reduce the partial or total occlusion ofthe artery by the collapse of arterial lining and to reduce the chanceof the development of thrombosis and restenosis, an expandable,intraluminal prosthesis, one example of which is a stent, is implantedin the lumen to maintain the vascular patency.

[0006] Stents act as scaffoldings, functioning to physically hold openand, if desired, to expand the wall of the passageway. Typically stentsare capable of being compressed, so that they can be inserted throughsmall cavities via catheters, and then expanded to a larger diameteronce they are at the desired location. Examples in the patent literaturedisclosing stents that have been applied in PTCA procedures include U.S.Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No. 4,800,882 issued toGianturco, and U.S. Pat. No. 4,886,062 issued to Wiktor. Mechanicalintervention via stents has reduced the rate of restenosis as comparedto balloon angioplasty. Yet, restenosis is still a significant clinicalproblem with rates ranging from 20-40%. When restenosis does occur inthe stented segment, its treatment can be challenging, as clinicaloptions are more limited as compared to lesions that were treated solelywith a balloon.

[0007] Stents are used not only for mechanical intervention but also asvehicles for providing biological therapy. Biological therapy can beachieved by medicating the stents. Medicated stents provide for thelocal administration of a therapeutic substance at the diseased site. Inorder to provide an efficacious concentration to the treated site,systemic administration of such medication often produces adverse oreven toxic side effects for the patient. Local delivery is a preferredmethod of treatment in that smaller total levels of medication areadministered in comparison to systemic dosages, but are concentrated ata specific site. Local delivery thus produces fewer side effects andachieves more favorable results. This invention provides for a stentcoating capable of sustained local delivery of therapeutic substancesand methods of forming the coating.

SUMMARY OF THE INVENTION

[0008] A method of coating a stent is provided. The method includesforming a first layer supported by a stent substrate and patterning thefirst layer by removing portions of the first layer.

[0009] In some embodiments, the method additionally includes forming aprimer layer on the surface of the stent substrate prior to forming thefirst layer.

[0010] In other embodiments, the method includes forming a second layeron the remaining portions of the first layer. The first layer maycontain a first substance and the second layer may contain a secondsubstance different than the first substance. The first and secondsubstances may be active ingredients, radiopaque elements, orradioactive isotopes.

[0011] In other embodiments, the act of patterning the first layerincludes forming a second layer on the surface of the stent prior toforming the first layer. The second layer is patterned to form vias inthe second layer. Such patterning may be performed by applying a laserdischarge to selected areas of the second layer. The first layer isformed on the remaining portions of the second layer and in the vias.The second layer is patterned to remove portions of the first layerdisposed on the remaining portion of the second layer to pattern thefirst layer.

[0012] In still other embodiments, the act of patterning the first layerincludes forming a second layer on the surface of the stent prior toforming the first layer and patterning the second layer to exposeportions of the surface of the stent. The act of patterning the firstlayer also includes forming depots in the stent between the remainingportions of the second layer, wherein the first layer fills the depots,and removing the remaining portions of the second layer to removeportions of the first layer disposed on the remaining portions of thesecond layer, wherein the first layer remains in the depots. A thirdlayer may be formed on the surface of the stent and over the first layerin the depots.

[0013] In still other embodiments, the act of patterning the first layerincludes forming a second layer on the first layer and patterning thesecond layer to form vias in the second layer to expose portions of thefirst layer. The act of patterning the first layer also includesremoving the exposed portions of the first layer, wherein portions ofthe first layer positioned underneath the remaining portions of thesecond layer remain essentially undisturbed, and removing the remainingportions of the second layer to form a patterned first layer. A thirdlayer may be formed on the remaining portions of the first layer.

[0014] A coated stent produced in accordance with the various methods isalso provided. The coated stent includes a first layer and adiscontinuous second layer separated by the first layer. The first layeris a discontinuous layer separated by the second layer so as to createan alternating pattern of the first and second layers on the surface ofthe stent. In accordance with another embodiment, the discontinuousfirst and second layers can be disposed on a primer layer.

BRIEF DESCRIPTION OF THE FIGURES

[0015]FIG. 1 illustrates a stent.

[0016] FIGS. 2A-2G illustrate a method of coating a stent in accordancewith several embodiments of the invention.

[0017] FIGS. 3A-3F illustrate a method of coating a stent in accordancewith several other embodiments of the invention.

[0018] FIGS. 4A-4F illustrate a method of coating a stent in accordancewith several other embodiments of the invention.

[0019] FIGS. 5A-5H illustrate a method of coating a stent in accordancewith several other embodiments of the invention.

DETAILED DESCRIPTION

[0020] “Polymer,” “poly,” and “polymeric” are defined as compounds thatare the product of a polymerization reaction and are inclusive ofhomopolymers, copolymers, terpolymers etc., including random,alternating, block, and graft variations thereof. Representativeexamples of polymers that can be used with the embodiments of thepresent invention include ethylene vinyl alcohol copolymer (commonlyknown by the generic name EVOH or by the trade name EVAL), polyhydroxyalkanoates such as (poly(hydroxyvalerate)), (poly(hydroxybutyrate)), and(poly(hydroxybutyrate-covalerate)); poly(L-lactic acid);polycaprolactone; poly(lactide-co-glycolide); polydioxanone;polyorthoester; polyanhydride; poly(glycolic acid); poly(D,L-lacticacid); poly(glycolic acid-co-trimethylene carbonate); polyphosphoester;polyphosphoester urethane; poly(amino acids); cyanoacrylates;poly(trimethylene carbonate); poly(iminocarbonate); copoly(ether-esters)(e.g. PEO/PLA); polyalkylene oxalates; polyphosphazenes and biomoleculessuch as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronicacid; polyurethanes; silicones; polyesters; polyolefins; polyisobutyleneand ethylene-alphaolefin copolymers; acrylic polymers and copolymers;vinyl halide polymers and copolymers, such as polyvinyl chloride;polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidenehalides, such as polyvinylidene fluoride and polyvinylidene chloride;polyacrylonitrile; polyvinyl ketones; polyvinyl aromatics, such aspolystyrene; polyvinyl esters, such as polyvinyl acetate; copolymers ofvinyl monomers with each other and olefins, such as ethylenemethylmethacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins,and ethylene-vinyl acetate copolymers; polyamides, such as Nylon 66 andpolycaprolactam; alkyd resins; polycarbonates; polyoxymethylenes;polyimides; polyethers; epoxy resins; polyurethanes; rayon;rayon-triacetate; cellulose; cellulose acetate; cellulose butyrate;cellulose acetate butyrate; cellophane; cellulose nitrate; cellulosepropionate; cellulose ethers; and carboxymethyl cellulose.

[0021] “Solvent” is defined as a liquid substance or composition whichis compatible with the polymer and is capable of dissolving the polymerat the concentration desired in the composition. Examples of solventsinclude, but are not limited to, dimethylsulfoxide (DMSO), chloroform,acetone, water (buffered saline), xylene, methanol, ethanol, 1-propanol,tetrahydrofuran, 1-butanone, dimethylformamide, dimethylacetamide,cyclohexanone, ethyl acetate, methylethylketone, propylene glycolmonomethylether, isopropanol, isopropanol admixed with water, N-methylpyrrolidinone, toluene, and combinations thereof.

[0022] The Figures have not been drawn to scale, and the dimensions suchas depth and thickness of the various regions and layers have been overor under emphasized for illustrative purposes. Referring to FIG. 1, astent 10 is illustrated, which is broadly defined to include any inter-or intraluminal device used for the release of an active ingredient, forupholding the luminal patency, and/or for the incorporation ofradiopaque or radioactive materials. Examples of stents includeself-expandable stents, balloon-expandable stents, and stent-grafts.Stent 10 can be made of a metallic material or an alloy such as, but notlimited to, stainless steel (316L), “MP35N,” “MP20N,” ELASTINITE(Nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy,gold, magnesium, or combinations thereof. “MP35N” and “MP20N” are tradenames for alloys of cobalt, nickel, chromium and molybdenum availablefrom standard Press Steel Co., Jenkintown, Pa. “MP35N” consists of 35%cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consistsof 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. Stents madefrom bioabsorbable or biostable polymers could also be used with theembodiments of the present invention.

[0023] FIGS. 2A-2G illustrate a method for coating stent 10 inaccordance with several embodiments of the invention. FIG. 2Aillustrates a segment of the body or substrate 12 of stent 10, whereinreference number 14 denotes the outer surface or the tissue contactingsurface of stent 10. The illustrations have been simplified for ease ofunderstanding and describing the embodiments of the present invention.FIG. 2B illustrates a first layer 16 formed on substrate 12. First layer16 can be of any suitable thickness. The thickness of first layer 16 canbe from about 0.1 micron to about 20 microns, more narrowly from about 2microns to about 10 microns. By way of example, first layer 16 can havea thickness of about 3 microns. First layer 16 can be made from apolymeric material. Polymers having a high coefficient of extinction,which allows the material to burn quickly and easily, can be used. Thecoefficient of extinction k is defined by Equation 1.

k={Ln(I ₀ /I _(f))}/h  (Equation 1)

[0024] Where

[0025] k=coefficient of extinction (cm⁻¹)

[0026] I₀=initial intensity

[0027] I_(f)=final intensity

[0028] h=distance at final intensity (cm)

[0029] A suitably high coefficient of extinction k can be greater thanor equal to 1×10⁴ cm⁻¹. Examples of polymers having such a coefficientof extinction include polyimide, segmented polyurethane, andpolycarbonate. Such polymers may be particularly suitable for preventingmelting defects when the patterning of first layer 16 is accomplishedusing a laser discharge as described below.

[0030] First layer 16 can be deposited by any conventional method suchas immersing substrate 12 in or spraying substrate 12 with a firstcomposition containing a dissolved mixture of a first solvent with afirst polymer and allowing the first solvent to evaporate from firstlayer 16. The polymer-solvent combination should be capable of formingfirst layer 16 as a uniform film, rather than in a powdered form, onsubstrate 12.

[0031] First layer 16, as illustrated in FIG. 2C, is patterned byremoving or etching portions of first layer 16 to form vias 18 to exposesurface 14 of substrate 12 not covered by first layer 16. Vias 18 can beformed by, for example, exposing first layer 16 to a laser dischargesuch as that produced by an excimer laser. The width of vias 18 isdependent on a variety of factors, such as the size of stent struts andthe coating pattern that is desired. By way of example, vias 18 can befrom about 5 microns to about 500 microns, for example about 100 micronswide.

[0032] Referring to FIG. 2D, a second layer 20, containing a firstsubstance, is deposited on substrate 12 to cover the remaining portionsof first layer 16 and vias 18. Second layer 20 can be made of anysuitable polymeric material and can be of any suitable thickness. Thethickness of second layer 20 can be from about 0.1 micron to about 15microns, more narrowly from about 1 micron to about 10 microns. By wayof example, second layer 20 can have a thickness of about 5 microns. Thepolymeric material for second layer 20 should possess good adhesivequalities to surface 14 of stent 10. If a radially expandable stent 10is used, the polymeric material should be capable of expanding withstent 10 without significant detachment or fragmenting of the materialfrom surface 14 of stent 10. The polymeric material should be abiocompatible polymer, either bio-stable or bio-absorbable in nature.One example of such a polymer is ethylene vinyl alcohol co-polymer.

[0033] Second layer 20 can be deposited by immersing substrate 12 in orspraying substrate 12 with a second composition containing a secondsolvent, a second polymer, and the first substance and allowing thesecond solvent to evaporate. The polymer-solvent combination selectedshould be capable of forming second layer 20 as a uniform film, ratherthan in a powdered form, on substrate 12. The second solvent should becapable of placing the polymer of the second layer 20 into solution butshould not be capable of removing the remaining portions of first layer16. In other words, the second solvent should not dissolve first layer16 during the application of the second composition.

[0034] Following the application of second layer 20, the remainingportions of first layer 16 can be removed, as illustrated in FIG. 2E, topattern second layer 20. The remaining portions of first layer 16 can beremoved by the application of a solvent, such as the first solvent usedto form first layer 16. The solvent should be capable of removing ordissolving the remaining portions of first layer 16. The polymericmaterial from which second layer 20 is made should not be capable ofbeing dissolved during the application of the solvent. Removal of theremaining portions of first layer 16 also causes the portions of secondlayer 20 that are disposed over first layer 16 to be physically removedor broken-off. Portions of second layer 20 that are in contact withsurface 14 remain attached to substrate 12.

[0035] Referring to FIG. 2F, a third layer 22, containing a secondsubstance, can be deposited on substrate 12 to cover the patternedsecond layer 20 and the exposed portions of surface 14. The secondsubstance can be the same as or different than the first substance.Third layer 22 can be deposited by applying a composition containing athird solvent, the second substance, and a polymeric material to stent10. The polymer-solvent combination selected should be capable offorming third layer 22 as a uniform film, rather than in a powderedform. The third solvent should not remove second layer 20 or adverselyaffect the first substance contained in the second layer 20. As anoptional step, as illustrated in FIG. 2G, the profile of third layer 22can be reduced so as to create an alternating pattern of second layer 20and third layer 22. The resulting stent 10 includes a low profilecoating defined by discontinuous second layer 20 interrupted by thirdlayer 22. The discontinuous second layer 20 and third layer 22 can carrya first and a second substance, respectively, for release of thesubstances at different rates in situ.

[0036] The first and second substances can be any active ingredientcapable of exerting a therapeutic or prophylactic effect in the practiceof the present invention. Examples of such active ingredients includeantiproliferative, antineoplastic, antiinflammatory, antiplatelet,anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, andantioxidant substances as well as combinations thereof.

[0037] A suitable example of an antiproliferative substance isactinomycin D, or derivatives and analogs thereof. Synonyms ofactinomycin D include dactinomycin, actinomycin IV, actinomycin I₁,actinomycin X₁, and actinomycin C₁. Examples of suitable antineoplasticsinclude paclitaxel and docetaxel. Examples of suitable antiplatelets,anticoagulants, antifibrins, and antithrombins include sodium heparin,low molecular weight heparin, hirudin, argatroban, forskolin, vapiprost,prostacyclin and prostacyclin analogs, dextran,D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole,glycoprotein IIb/IIIa platelet membrane receptor antagonist, recombinanthirudin, thrombin inhibitor (available from Biogen), and 7E-3B® (anantiplatelet drug from Centocore). Examples of suitable antimitoticagents include methotrexate, azathioprine, vincristine, vinblastine,fluorouracil, adriamycin, and mitamycin. Examples of suitable cytostaticor antiproliferative agents include angiopeptin (a somatostatin analogfrom Ibsen), angiotensin converting enzyme inhibitors such as CAPTOPRIL(available from Squibb), CILAZAPRIL (available from Hoffman-LaRoche), orLISINOPRIL (available from Merck); calcium channel blockers (such asNifedipine), colchicine, fibroblast growth factor (FGF) antagonists,fish oil (omega 3-fatty acid), histamine antagonist, LOVASTATIN (aninhibitor of HMG-CoA reductase, a cholesterol lowering drug from Merck),monoclonal antibodies (such as PDGF receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitor (available formGlazo), Surmin (a PDGF antagonist), serotonin blockers, steroids,thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), andnitric oxide. Other therapeutic substances or agents which may beappropriate include alpha-interferon, genetically engineered epithelialcells, and dexamethasone. Exposure of the composition to the activeingredient is not permitted to adversely alter the active ingredient'scomposition or characteristic. Accordingly, the particular activeingredient is selected for compatibility with the blendedpolymer-solvent.

[0038] The dosage or concentration of the active ingredient required toproduce a favorable therapeutic effect should be less than the level atwhich the active ingredient produces toxic effects and greater than thelevel at which non-therapeutic results are obtained. The dosage orconcentration of the active ingredient required can depend upon factorssuch as the particular circumstances of the patient; the nature of thetrauma; the nature of the therapy desired; the time over which theingredient administered resides at the treatment site; and if otherbioactive substances are employed, the nature and type of the substanceor combination of substances. Therapeutic effective dosages can bedetermined empirically, for example by infusing vessels from suitableanimal model systems and using immunohistochemical, fluorescent orelectron microscopy methods to detect the agent and its effects, or byconducting suitable in vitro studies. Standard pharmacological testprocedures to determine dosages are understood by one of ordinary skillin the art.

[0039] In accordance with another embodiment, the first and/or secondsubstances can be radiopaque elements or radioactive isotopes. Examplesof radiopaque elements include, but are not limited to, gold, tantalum,and platinum. An example of a radioactive isotope is P³². Sufficientamounts of such substances may be dispersed in the composition. Bydispersed it is meant that the substances are not present in thecomposition as agglomerates or flocs. Certain substances will dispersewith ordinary mixing, such as by stirring with a stir bar, vortexing,and similar perturbation techniques. Otherwise, the substances can bedispersed by high shear processes such as ball mill, disc mill, sandmill, attritor, rotor stator mixer, or ultrasonication—all such highshear dispersion techniques being well known to one of ordinary skill inthe art. Agents in the form of surfactants, emulsifiers, or stablilizersmay also be added to the composition to assist in dispersion.

[0040] Referring to FIGS. 3A-3F, an optional primer layer 24, free fromany substances, can be formed on surface 14 of substrate 12 prior to theformation of first layer 16. The presence of a substance in second layer20 can interfere with the ability of second layer 20 to adhereeffectively to surface 14 of substrate 12. High drug loadings of 10-40%by weight in the matrix may significantly hinder the retention of secondlayer 20 on surface 14 of substrate 12. The primer layer 24 serves as afunctionally useful intermediary layer between surface 14 of substrate12 and the substance-containing second layer 20. The primer layer 24provides for an adhesive tie which, in effect, would also allow for thequantity of the substance in the second layer 20 to be increased withoutcompromising the ability of second layer 20 to be effectively containedon substrate 12 during delivery and, if applicable, expansion of stent10.

[0041] With the use of thermoplastic polymers such as, but not limitedto, ethylene vinyl alcohol copolymer, polycaprolactone,poly(lactide-co-glycolide), and poly(hydroxybutyrate), the depositedprimer composition should be exposed to a heat treatment at atemperature range greater than about the glass transition temperature(T_(g)) and less than about the melting temperature (T_(m)) of theselected polymer. Unexpected results have been discovered with treatmentof the composition under this temperature range, specifically strongadhesion or bonding of the coating to the metallic surface of a stent10. The prosthesis should be exposed to the heat treatment for anysuitable duration of time that will allow for the formation of primerlayer 24 on surface 14 of substrate 12 and for the evaporation of thesolvent employed.

[0042] FIGS. 3A-3F correspond to the above-described FIGS. 2B-2G,respectively, but for the initial formation of primer layer 24 directlyonto surface 14 of substrate 12. Briefly, FIG. 3A illustrates theformation of first layer 16 on primer layer 24. First layer 16 ispatterned to form vias 18, as depicted in FIG. 3B. The underlying primerlayer 24 should remain essentially undisturbed on surface 14 ofsubstrate 12. In FIG. 3C, second layer 20, containing a first substance,is deposited on the substrate 12 to cover the remaining portions offirst layer 16 and vias 18. The polymeric material selected for secondlayer 20 should possess good adhesive qualities to primer layer 24.Following the application of second layer 20, the remaining portions offirst layer 16 are removed, as illustrated in FIG. 3D, to pattern secondlayer 20. Referring to FIG. 3E, a third layer 22, containing a secondsubstance, can be deposited on second layer 20. The second substance canbe the same as or different than the first substance. As an optionalstep, as illustrated in FIG. 3F, the profile of third layer 22 can bereduced so as to create an alternating pattern of second layer 20 andthird layer 22, being adhesively tied to stent 10 via primer layer 24,and containing a combination of first and second substances that arecapable of being released at different rates in situ.

[0043] FIGS. 4A-4F illustrate a method of coating stent 10 in accordancewith several other embodiments of the present invention. FIG. 4Aillustrates first layer 16 formed on substrate 12. First layer 16 may bemade from any suitable material and can be of any suitable thickness.The thickness of first layer 16 can be from about 0.5 micron to about 10microns, more narrowly from about 2 microns to about 8 microns. By wayof example, first layer 16 can have a thickness of about 3 microns.First layer 16 can be made from a polymeric material. Polymers having ahigh coefficient of extinction, as discussed above, are suitable. Firstlayer 16 can be deposited by any conventional method such as immersingsubstrate 12 in or spraying substrate 12 with a first compositioncontaining a dissolved mixture of a first solvent with the polymer andallowing the first solvent to evaporate from first layer 16.

[0044] First layer 16, as illustrated in FIG. 4B, is patterned byremoving or etching portions of first layer 16 to form vias 18.Additionally, portions of substrate 12 underlying the removed portionsof first layer 16 are removed or etched to form depots 26. Depots 26 canbe formed by, for example, exposing first layer 16 and the underlyingsubstrate 12 to a laser discharge such as that produced by an excimerlaser.

[0045] Referring to FIG. 4C, a second layer 20, containing a firstsubstance, is deposited on the substrate 12 to fill depots 26 and vias18 and to cover the remaining portions of first layer 16. Second layer20 can be made of a polymeric material having good adhesive qualities tosubstrate 12. One example of such a polymer is ethylene vinyl alcoholco-polymer.

[0046] Following the application of second layer 20, the remainingportions of first layer 16 are removed, as illustrated in FIG. 4D, topattern second layer 20. The remaining portions of first layer 16 can beremoved by the application of a solvent, such as the first solvent usedto form first layer 16. The polymeric material from which second layer20 is made should not be capable of being removed or dissolved duringthe application of the solvent. Removal of the remaining portions offirst layer 16 also causes the portions of second layer 20 that aredisposed over first layer 16 to be physically removed or broken-off.Portions of second layer 20 that are within depots 26 remain attached tosubstrate 12. As illustrated in FIG. 4E, the profile of second layer 20can be reduced so as to remove the portions of second layer 20 extendingabove surface 14.

[0047] Referring to FIG. 4F, in accordance with another embodiment, athird layer 22 containing a second substance, can be deposited onsubstrate 12 to cover second layer 20 within depots 26 as well assurface 14. The second substance can be the same as or different thanthe first substance. Third layer 22 can be made of any suitablepolymeric material and can be of any suitable thickness. The thicknessof third layer 22 can be from about 0.2 microns to about 10 microns,more narrowly from about 2 microns to about 8 microns. By way ofexample, third layer 22 can have a thickness of about 5 microns. Theresulting stent 10 includes a first substance within depots 26 and asecond substance in third layer 22, each of which is capable of beingreleased at a different rate in situ.

[0048] FIGS. 5A-5H illustrate a method of coating stent 10 in accordancewith other embodiments of the present invention. FIG. 5A illustrates afirst layer 28, containing a first substance. The thickness of firstlayer 28 can be from about 0.2 micron to about 10 micron, more narrowlyfrom about 2 microns to about 8 microns. By way of example, first layer28 can have a thickness of about 5 microns. FIG. 5B illustrates a secondlayer 30 formed on substrate 12 to cover first layer 28. The thicknessof second layer 30 can be from about 1 micron to about 10 microns, morenarrowly from about 2 microns to about 8 microns. By way of example,second layer 30 can have a thickness of about 4 microns. Second layer 30can be made from a polymeric material such as, but not limited to,polyurethanes or parylene.

[0049] Second layer 30, as illustrated in FIG. 5C, is patterned byremoving portions of second layer 30 to form vias 18, to expose portionsof first layer 28 not covered by second layer 30. Vias 18 can be formedby, for example, exposing second layer 30 to a laser discharge. Firstlayer 28 is patterned by removing portions of first layer 28 not coveredby the remaining portions of second layer 20, as illustrated in FIG. 5D.First layer 28 can be patterned by exposing the uncovered portions offirst layer 28 to a solvent so as to remove or dissolve the selectedportions of first layer 28.

[0050] The remaining portions of second layer 30 can be removed, asillustrated in FIG. 5E by, for example, exposing second layer 30 to alaser discharge. Alternatively, the remaining portions of second layer30 can be removed by the application of a solvent. The solvent should becapable of removing or dissolving the remaining portions of second layer20, but should not remove the polymeric material from which first layer28 is made or adversely affect the first substance.

[0051] Referring to FIG. 5F, a third layer 32, containing a secondsubstance, is deposited on substrate 12 to cover the remaining portionof first layer 28 and vias 18. Third layer 32 can be made of anysuitable polymeric material and can be of any suitable thickness. Thesolvent used to form third layer 32 should be capable of placing thepolymer of the third layer 32 into solution, but should not be capableof removing the remaining portions of first layer 28. In other words,the solvent should not dissolve first layer 28 during the application ofthe third solution.

[0052] Following the application of third layer 32, the profile of thirdlayer 32 can optionally be reduced so as to create an alternatingpattern of first layer 28 and third layer 32 having essentially the samethickness, as depicted in FIG. 5G. As another optional step, a fourthlayer 34 can be deposited on the alternating pattern of first layer 28and third layer 32, as illustrated in FIG. 5H. In some embodiments,fourth layer 34 functions as a diffusion barrier for the first andsecond substances in first layer 28 and third layer 32, respectively.Fourth layer 34 can also contain a third substance. The third substancecan be the same as or different than the first and second substances.The resulting stent 10 includes a low profile coating having acombination of first, second and third substances that are capable ofbeing released at different rates in situ. In yet another embodiment, aprimer layer (not shown) can also be employed.

[0053] In the above-described embodiments, high temperature heating in afurnace (e.g., 700-800° C.) may be employed to incinerate all polymerson substrate 12. This polymer removal technique is particularly suitablewhen gold or platinum has been deposited as the first substance.

[0054] In accordance with the above-described methods, one or moreactive ingredient can be applied to a device, e.g., a stent, retained onthe stent during delivery and expansion of the stent, and released at adesired control rate and for a predetermined duration of time at thesite of implantation. A stent having the above-described coating isuseful for a variety of medical procedures, including, by way ofexample, treatment of obstructions caused by tumors in bile ducts,esophagus, trachea/bronchi and other biological passageways. A stenthaving the above-described coating is particularly useful for treatingoccluded regions of blood vessels caused by abnormal or inappropriatemigration and proliferation of smooth muscle cells, thrombosis, orrestenosis. Stents may be placed in a wide array of blood vessels, botharteries and veins. Representative examples of sites include the iliac,renal, and coronary arteries.

[0055] Briefly, an angiogram is first performed to determine theappropriate positioning for stent therapy. Angiography is typicallyaccomplished by injecting a radiopaque contrast agent through a catheterinserted into an artery or vein as an x-ray is taken. A guidewire isthen advanced through the lesion or proposed site of treatment. Over theguidewire is passed a delivery catheter which allows a stent in itscollapsed configuration to be inserted into the passageway. The deliverycatheter is inserted either percutaneously or by surgery into thefemoral artery, brachial artery, femoral vein, or brachial vein, andadvanced into the appropriate blood vessel by steering the catheterthrough the vascular system under fluoroscopic guidance. A stent havingthe above-described coating may then be expanded at the desired area oftreatment. A post insertion angiogram may also be utilized to confirmappropriate positioning.

[0056] While particular embodiments of the present invention have beenshown and described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects and, therefore, the appended claims areto encompass within their scope all such changes and modifications asfall within the true spirit and scope of this invention.

What is claimed is:
 1. A method of coating a stent, comprising: (a)forming a first layer supported by a stent substrate; and (b) patterningsaid first layer by removing portions of said first layer.
 2. A coatedstent produced in accordance with the method of claim
 1. 3. The methodof claim 1, wherein said patterning comprises: (a) forming a secondlayer on the surface of said stent prior to forming said first layer;(b) patterning said second layer to form vias in said second layer,wherein said first layer is formed on the remaining portions of saidsecond layer and in said vias; and (c) patterning said second layer toremove portions of said the first layer disposed on the remainingportion of said second layer to pattern said first layer.
 4. The methodof claim 1, additionally comprising forming a primer layer on thesurface of said stent substrate prior to forming said first layer,wherein said patterning comprises: (a) forming a second layer on saidprimer layer prior to forming said first layer; (b) patterning saidsecond layer to form vias in said second layer, wherein said primerlayer remains essentially undisturbed on the surface of said stentsubstrate, and wherein said first layer is formed on the remainingportions of said second layer and in said vias on said primer layer; and(c) removing the remaining portions of said second layer to removeportions of said first layer disposed on the remaining portions of saidsecond layer to pattern said first layer.
 5. The method of claim 1,additionally comprising forming a second layer on the remaining portionsof said first layer.
 6. The method of claim 5, wherein said first layercontains a first substance and said second layer contains a secondsubstance different than said first substance.
 7. The method of claim 6,wherein said first or second substances are selected from a group oftherapeutic agents, radiopaque elements and radioactive isotopes.
 8. Themethod of claim 1, wherein said patterning comprises: (a) forming asecond layer on the surface of said stent prior to forming said firstlayer; (b) patterning said second layer to expose portions of thesurface of said stent; (c) forming depots in said stent between theremaining portions of said second layer, wherein said first layer fillssaid depots; and (d) removing the remaining portions of said secondlayer to remove portions of said first layer disposed on the remainingportions of said second layer, wherein said first layer remains in saiddepots.
 9. The method of claim 8, additionally comprising reducing theprofile of said first layer such that said first layer does not protrudeout from said depots.
 10. The method of claim 8, additionally comprisingforming a third layer over said first layer and on the surface of saidstent.
 11. The method of claim 10, wherein said first layer contains afirst substance and said third layer contains a second substancedifferent from said first substance.
 12. The method of claim 1, whereinsaid patterning comprises: (a) forming a second layer on said firstlayer; (b) patterning said second layer to form vias in said secondlayer to expose portions of said first layer; (c) removing the exposedportions of said first layer, wherein portions of said first layerpositioned underneath the remaining portions of said second layer remainessentially undisturbed; and (d) removing the remaining portions of saidsecond layer to form a patterned first layer.
 13. The method of claim12, additionally comprising forming a third layer on the remainingportions of said first layer.
 14. The method of claim 13, additionallycomprising reducing the profile of said third layer so as to create analternating pattern of said first layer and said third layer.
 15. Themethod of claim 13, wherein said first layer contains a first substanceand said third layer contains a second substance different from saidfirst substance.
 16. The method of claim 12, wherein the coatingcomprises a discontinuous first layer interrupted by a second layer. 17.A coating for a stent comprising: a first layer; and a discontinuoussecond layer separated by said first layer.
 18. The coating of claim 17,wherein said first layer is a discontinuous layer separated by saidsecond layer so as to create an alternating pattern of said first layerand said second layer disposed on the surface of the stent.
 19. Thecoating of claim 17, additionally comprising: a primer layer disposed onthe surface of the stent, wherein said first layer is a discontinuouslayer separated by said second layer so as to create an alternatingpattern of said first layer and said second layer disposed on saidprimer layer.
 20. The coating of claim 17, wherein said first layercontains a first substance and said second layer contains a secondsubstance, and wherein the release rate of said first substance isdifferent than the release rate of said second substance.
 21. Thecoating of claim 17, wherein said first substance is different than saidsecond substance.
 22. The coating of claim 17, wherein the stent is aradially expandable stent.